Estrogens have been shown to play an important role in the modulation of estrogen receptor positive breast carcinoma. Binding of endogenous estrogens, in particular 17xcex2-estradiol (E2), to the estrogen receptor has been linked to proliferation of the carcinoma cells, by causing the carcinoma cells to shift from the G1 phase of the cell cycle to the S phase of the cell cycle. The G1 stage of interphase is characterized by the cell being in a resting state, whereas it is during the S phase that the DNA synthesis necessary for cell survival and proliferation occurs.
Current trends in the treatment of estrogen receptor positive breast carcinoma are focused on the use of anti-estrogenic agents that prevent the binding of E2 to the estrogen receptor. It has been postulated that an anti-estrogen may inhibit E2 binding through competitive inhibition at the estrogen receptor or alternatively by binding to another site such as the anti-estrogen or calmodulin receptor, thereby preventing the binding of E2 to the estrogen receptor. [V. C. Jordan, Pharmacol Rev 36: 245 (1984)]. In one study, approximately 60% of patients with estrogen receptor positive breast cancer ( greater than 10 femtomol/mg cytosol protein) responded to anti-estrogen therapy, whereas less than 10% of patients with estrogen receptor negative tumors ( less than 10 femtomol/mg cytosol protein) responded. [J. L. Borgna, Biochem Pharmacol 31: 3187 (1982)]. Treatment of the estrogen receptor positive MCF-7 human breast cancer cells with tamoxifen [Z-1-(4xcex2-dimethylaminoethoxyphenyl) 1,2-diphenylbut-1-ene citrate], a non-steroidal anti-estrogen, has been shown to inhibit cell E2 stimulated cell growth by virtue of its ability to prevent the MCF-7 cells from entering the S phase of the cell cycle. [N. Brunner, Cancer Res 49: 1515 (1989)]. Chronic administration of tamoxifen (200 xcexcg/day for 3 weeks) to mature female rats with dimethylbenzanthracene (DMBA) induced tumors prevents the accumulation of administered [3H]-E2 in uterine, vaginal, and mammary tumor tissue. [V. C. Jordan, J Endocr 68: 297 (1976)]. Presently, the treatment of choice for postmenopausal estrogen receptor positive breast carcinoma is tamoxifen. [V. C. Jordan, Pharmacol Rev 36: 245 (1984); A. U. Buzdar, Cancer 62: 2098, (1988); V. Hug, Br J Cancer 59: 421, (1989)].
Positive results with tamoxifen have been reported in several estrogen receptor positive ovarian carcinoma cell lines. [S. P. Langdon, J Endocrin 127(Supp): 119 (1990); G. dePalo, Acta Oncol 28: 163 (1989); K. R. Geisinger, Cancer 65: 1055 (1990); S. P. Langdon, Br J Cancer 62: 213 (1990)]. In addition, tamoxifen produced positive results in inhibiting the growth of several other estrogen receptor positive carcinomas including, DMBA-induced uterine adenocarcinoma in rats [S. Sekiya, J Obstet Gynaec Br Commonw 83: 183 (1976)]; Dunning R3327 rat prostrate adenocarcinoma [M. M. Ip, Cancer Res 40: 2188 (1980)]; and diethylstilbesterol induced renal tumors in hamsters [A. H. Dodge, Eur J Cancer Clin Oncol 13: 1377 (1977)].
In humans, tamoxifen has been used with varying degrees of success to treat a variety of estrogen receptor positive carcinomas such as breast cancer, endometrial carcinoma, prostate carcinoma, ovarian carcinoma, renal carcinoma, melanoma, colorectal tumors, desmoid tumors, pancreatic carcinoma, and pituitary tumors. [B. J. Furr, Pharmac Ther 25: 127 (1984)].